Immunotherapy of lymphoma through in situ manipulation of an involved lymph node can allow for development of an active anti-lymphoma immune response without the need for ex vivo handling or immunization with a specific antigen. A comprehensive and successful approach to in situ immunization in lymphoma would require effective presentation of antigen by the lymphoma cells or professional antigenpresenting cells, activation of lymphoma-specific T cells and suppression of the regulatory arm of the immune response to enhance development of a sustained anti-lymphoma T cell response. The current proposal evaluating a novel approach to in situ immunization is based on scientific advances made possible through the UI/MC SPORE over the prior funding period. The overall hypothesis is that in situ immunization with nanoparticles will allow for induction and maintenance of a robust anti-lymphoma immune response with acceptable toxicity. To test this hypothesis, this project will assess the effect of intratumoral injection of nanoparticles (NPs) containing doxorubicin (dox) on lymphoma cells, the immune microenvironment, and the anti-lymphoma immune response in animal models and in a Phase I clinical trial in subjects with lymphoma. It will then assess the effect of intratumoral injection of NPs containing both dox and the toll-like receptor 9 (TLR9) agonist CpG ODN (CpG dox NPs) in mice and humans. Finally, it will assess how agents capable of maintaining the T cell response impact on the success of in situ immunization with NP. Successful development of such an approach to in situ immunization would be of great significance as a way to treat lymphoma, and could be applicable to other cancers as well.